delta8(9)-7-keto-11-oxy-steroids and processes of preparing them



United States Patent A -7-KETO-1I-OXY-STEROIDS AND PROCESSES OF PREPARING THEM John M. Chemerda, Metuchen, N.J., assignor to Merck & Co., Inc., Rahway, NJ., a corporation of New Jersey No Drawing. Application December 30, 1955 Serial No. 556,481

24 Claims. (Cl. 260-23955) This invention is concerned generally with steroid compounds having an oxygen atom attached to the carbon atom in the ll-position of the molecule, and with proccases for preparing these ll-oxygenated steroid compounds. More particularly, it relates A -7-keto-11- (keto, hydroxy or acyloxy) cyclopentanopolyhydrophenanthrene compounds and with the processes for preparing these compounds starting with the corresponding A -7-keto-cyclopentanopolyhydrophenanthrene compound. The A -7-keto-11-(keto, hydroxy or acyloxy) cyclopentanopolyhydrophenanthrene compounds thus obtained are valuable as intermediates in the synthesis of steroid hormones having an oxygen atom attached to the ll-carbon atom, such as the adrenal hormones, corticosterone, cortisone and Compound F.

This application is a continuation-in-part of my copending application, Serial No. 240,052, filed August 2,

1951, now Patent No. 2,734,897.

The A -7-keto-1l-(keto, hydroxy or acyloxy)-cyclopentanopolyhydrophenanthrene compounds, subject of the present invention, have at rings B and C the following chemical structure:

wherein R is a keto, hydroxy or acyloxy radical.

These A 7-keto-ll-(keto, hydroxy or acyloxy)- cyclopentanopolyhydrophenanthrene compounds can be prepared as follows: a A -7 keto-cyclopentanopolyhydrophenanthrene compound (Compound 1 hereinbelow), a A -7-keto-cyclopentanopolyhydrophenanthrene compound (Compound 2), or a mixture of these compounds, is reacted with an acylating agent to produce the corresponding enol acylate, that is, the A' -7- acyloxy cyclopentanopolyhydrophenanthrene compound (Compound 3); the latter compound is treated with an organic per-acid, whereby the double bond connecting the 9- and 11-carbon atoms is replaced by a 9,11-epoxide linkage, thereby forming the corresponding ,A -7-acyloxy- 9,11 epoxy cyclopentanopolyhydrophenanthrene compound (Compound 4). This compound is converted by reaction with a hydrolyzing agent such "as an alcoholic solution of an alkali metal hydroxide to the corresponding A -7-keto-11-hydroxy cyclopentanopolyhydrophenanthrene compound (Compound This A -7-ket0- 2,919,270 Patented Dec. 29, 1959 Compound 1 Compound 2 Aeylating Acylating l agent. ag n l Organic 0 per-acid Compound 4 alkali metal hydroxide Compound 5 I Alcoholic Strong oxidizing agent Oompound 7 agent Compound 6 l Acylating wherein R represents an acyl radical.

invented process are those having a sterol side chain attached to the carbon atom in the 17-position of the molecule such as 43 -7-keto-ergostadiene, A -7- keto ergostadiene, Aw),22 3 hydroxy 7 ketoergostadiene, M 3 hydroxy 7 keto ergostadiene, A 7 keto cholestene, A9(11) 7 ketocholestene, 13 3 hydroxy 7 keto cholestene, A 3 hydroxy 7 keto stigmastadiene, A 3-hydroxy-7-keto-stigmastadiene, a bile acid side chain attached to the 17-carbon atom such as A -3-hydroxy- 7 keto cholenic acid, A9(11) 3 hydroxy 7 ketocholenic acid, A -3-hydroxy-7-keto-allocholenic acid, A -3-hydroxy-7-keto-allocholenic acid, a degraded bile acid side chain attached to the 17-carbon atom such as A -3-hydroxy-7-keto-bisnorcholenic acid, A 3 hydroxy 7 keto bisnorcholenic acid, A 3- hydroxy-7-keto-bisnorallocholenic acid, A -3-hydroxy- 7-keto-bisnorallocholenic acid, a 17-carboxyl substituent such as A -7-keto-etiocholenic acid, A 1).-7-ket0- etiocholenic acid, A 7 keto etioallocholenic acid, A -7-keto-etioallocholenic acid, a 17-acetyl substituent such as A -3-hydroXy-7-keto-pregnene, A -3- hydroxy 7 keto allopregnene, a sapogenin side chain such as A -7-keto-dehydrotigonenin, A -7-keto-dehydrotigogenin, as well as A or A )-7-keto-cyclopentanopolyhydrophenanthrene compounds having a hydroxy substituent in the 3-position of the molecule esterified by an acyl substituent, and the like.

In preparing these A -7-keto-cyclopentanopolyhydrophenanthrene compounds, we ordinarily start with the corresponding 13 -cyclopentanopolyhydrophenanthrene compounds, certain of which, such as ergosterol D and 3-acyloxy derivatives thereof, are described in the prior art. Other n' -cyclopentanopolyhydrophenanthrene compounds can be prepared, starting with readily available A -cyclopentanopolyhydrophenanthrene compounds such as cholesterol, by treating said A cyclopentanopolyhydrophenanthrene compound (Compound 9 hereinbelow) with bromosuccinimide, reacting the resulting A -7-bromo-cycl0pentanopolyhydrophenanthrene compound (Compound 10) With a tertiary amine to form the corresponding A cyclopentanopolyhydrophenanthrene compound (Com pound 11), reacting this compound with hydrogen in the presence of Raney nickel catalyst thereby selectively reducing the unsaturated linkage attached to the carbon atom in the 5-position to form the corresponding A cyclopentanopolyhydrophenanthrene compound (Compound 12) and bringing said n' -cyclopentanopolyhydrophenanthrene compound into intimate contact with a solution of mercuric acetate in acetic acid thereby producing the corresponding A -cyclopentanopolyhydrophenanthrene compound (Compound 13). The reactions indicated hereinabove may be chemically represented (insofar as rings B and C are concerned) as follows:

I/ Bromosuceinimide i l l /\J Compound 9 Compound 10 Tertiary amine L/ Hydrogen Rane Compound 13 These Amul) cyclopentanopolyhydrophenanthrene compounds can then be converted to the desired A 0r 9(11) 7 keto cyclopentanopolyhydrophenanthrene compounds (utilized as starting materials in the presently invented process) as follows: the A' -cyclopentanopolyhydrophenanthrene compound (Compound 13) is reacted with osmium tetroxide and the intermediate osmate ester is hydrolyzed, preferably by treatment with aqueous sodium sulfite, to form the corresponding A 7,8 dihydroxy cyclopentanopolyhydrophenanthrene compound (Compound 14) and/or A -9,11-dihydroxycyclopentanopolyhydrophenanthrene compound (Compound 15). Either of these compounds, or a mixture thereof, is then reacted with an aqueous acidic solution at a temperature between about room temperature and C. to produce a mixture of the desired A 7 keto cyclopenttanopolyhydrophenanthrene compound (Compound 1) and A -7-keto-cyclopentanopolyhydrophenanthrene compound (Compound 2).

Alternatively, the A1901) -cyclopentanopolyhydrophenanthrene compound can be reacted with perbenzoic acid to form the corresponding A -9,11-epoxy-cyclopentanopolyhydrophenanthrene compound (Compound 16) and/or the corresponding A -7,8-epoxy-cyclopentanopolyhydrophenanthrene compound (Compound 17). Either of these compounds or a mixture thereof can be reacted with an aqueous acidic solution at a temperature between room temperature and 100 C. to form the desired A -7-keto-cyclopentanopolyhydrophenanthrene compound If desired, the A -cyclopentanopolyhydrophenanthrene epoxide compound can be suspended in a liquid medium such as an alkanoic anhydride, xylene, and the like, and the suspension heated at a temperature of about C. thereby forming directly the corresponding A -7-keto-cyclopentanopolyhydrophenanthrene compound (Compounds 1 and 2). Instead of isolating the A -7-keto-cyclopentanopolyhydrophenanthrene compound, the reaction mixture can be heated, without purification, with an alkanoyl chloride thereby forming the corresponding enol acylate, the A719(11) 7 acyloxy-cyclopentanopolyhydrophenanthrene compound (Compound 3 on page 4 hereinabove). The reaction indicated hereinabove may be chemically represented (with respect to the chemical changes occurring in rings B and C) as follows:

(1) Osmium tetroxide H (2) Hydrolyzing agent H Compound 13 Compound 14 Compound Perbenzoic Aqueous acid acid Aqueous acid and/or oillfilkgrngic t O o a y 1 e a 0. FiCompound 16 Corupoundil Compound 1 Compound 2 .Alkanoic anhydride alkanoyl chloride Compound 3 The A -7-keto-cyclopentanopolyln drophenanthrene starting material is reacted with an acylating agent to produce the corresponding enol acylate, the A7301) 7 acyloxy cyclopentanopolyhydrophenanthrene compound. This acylation reaction is ordinarily carried out by bringing the A -7-keto-cyclopentanopolyhydrophenanthrene compound into intimate contact with said acylating agent, preferably a lower alkanoic anhydride such as acetic anhydride, propanoic anhydride, and the like, in the presence of a catalyst such as acetyl chloride, p-toluene sulfonic acid, pyridine and the like, thereby forming said A -7-acyloxy-cyclopentanopolyhydrophenanthrene compound such as A -7-acyloxyergostatriene, A 3,7 diacyloxy ergostatriene, A 3,7 dialkanoxy ergostatriene, A 3,7 diacetoxy ergostatriene, Awul) 7 acyloxychlolestadiene, A1901) 3,7 diacyloxy cholestadiene, A1901) 3,7 dialkanoxy cholestadiene, A 3,7- diacetoxy cholestadiene, A' 3,7 diacyloxystigmastatriene, A -3,7-dialkanoxy-stigrnastatriene, A 3,7 diacetoxy stigmastatriene, A 3,7 diacyloxy choladienic acid, Algal) 3,7 dialkanoxy choladienic acid, A1901) 3,7 diacetoxy chloladienic acid, A7301) 3,7 diacyloxy allocholadienic acid, A1901) 3,7 dialkanoxy allocholadienic acid, A 3,7 diacetoxy allocholadienic acid, A 3,7 diacyloxy bisnorcholadienic acid, A7901) 3,7- dialkanoxy bisnorcholadienic acid, A 3,7 diacetoxy bisnorcholadienic acid, A1901) 3,7 diacyloxybisnorallo choladienic acid, A' 3,7 dialkanoxybisnorallo choladienic acid, A' 3,7 diacetoxybisnorallo choladienic acid, A7301) 3,7 diacyloxyetiocholadienic acid, A' 3,7 diacyloxy etioallocholadienic acid, A' 3,7 diacyloxy pregnadiene, A7301) 3,7 dialkanoxy pregnadiene, A7301) 3,7- diacetoxy pregnadiene, A1901) 3,7 diacyloxy allopregnadiene, A' 3,7 dialkanoxy allopregnadiene, A1901) 3,7 diacetoxy allopregnadiene, A 7 acyloxy dehydrotigogenin acylate, A 7 alkanoxy dehydrotigogenin alkanoate, A1901) 7 acetoxydehydrotigogenin acetate, and the like.

The Amul) 7 acyloxy cyclopentanopolyhydrophenanthrene compound is then reacted with an organic peracid such as perbenzoic acid, perphthalic acid, and the like, thereby forming the corresponding A 7- acyloxy 9,11 epoxy cyclopentanopolyhydrophenanthrene compound. This reaction is conveniently conducted by bringing the reactants together in an organic liquid medium such as benzene, and preferably at about room temperature. The A 7 acyloxy 9,11 epoxycyclopentanopolyhydrophenanthrene compounds which can be prepared in accordance with this procedure include the following: A 7 acyloxy 9,11 epoxyergostadiene, A 3,7 diacyloxy 9,11 epoxyergostadiene, A 3,7 dialkanoxy 9,11 epoxyergostadiene, A7122 3,7 diacetoxy 9,11 epoxyergostadiene, A 7 acyloxy 9,11 epoxy cholestene, A 3,7 diacyloxy 9,11 epoxy cholestene, A 3,7- dialkanoxy 9,11 epoxy cholestene, A 3,7 diacetoxy 9,11 epoxy cholestene, A 3,7 diacyloxy- 9,11 epoxy stigmastadiene, A 3,7 dialkanoxy- 9,11 epoxy stigmastadiene, A' 3,7 diacetoxy- 9,11 epoxy stigmastadiene, A 3,7 diacyloxy- 9,l1 epoxy cholenic acid, A 3,7 dialkanoxy- 9,11 epoxy cholenic acid, A' 3,7 diacetoxy- 9,11 epoxy cholenic acid, A 3,7 diacyloxy- 9,1l epoxy allocholenic acid, A 3,7 dialkanoxy- 9,11 epoxy allocholenic acid, A' 3,7 diacetoxy- 9,11 epoxy allocholenic acid, A 3,7 diacyloxy- 9,11 epoxy bisnorcholenic acid, A 3,7 dialkanoxy- 9,11 epoxy bisnorcholenic acid, A 3,7 diacetoxy- 9,l1 epoxy bisnorcholenic acid, A 3,7 diacyloxy- 9,l1 epoxy bisnorallocholenic acid, A' -3,7 dialkanoxy 9,11 epoxy bisnorallocholenic acid, A 3,7- diacetoxy 9,11 epoxy bisnorallocholenic acid, A"- 3,7 diacyloxy 9,11 epoxy etiocholem'c acid, N- 3,7 diacyloxy 9,11 epoxy etioallocholenic acid, N- 3,7 diacyloxy 9,11 epoxy pregnene, A 3,7 dialkanoxy 9,11 epoxy pregnene, A 3,7 diacetoxy- 9,11 epoxy pregnene, A 3,7 diacyloxy 9,11- epoxy allopregnene, A 3,7 dialkanoxy 9,11- epoxy allopregnene, A" 3,7 diacetoxy 9,11 epoxyallopregnene, A 7 acyloxy 9,11 epoxy dehydrotigogenin acylate, A 7 alkanoxy 9,11 epoxydehydrotigogenin alkanoate, A 7 acetoxy 9,11 epoxydehydrotigogenin acetate, and the like.

The A -7acyloxy-9,11-epoxy-cyclopentanopolyhydrophenanthrene compound is then reacted with an alcoholic solution of an alkali metal hydroxide, such as ethanolic potassium hydroxide, methanolic potassium hydroxide, methanolic sodium hydroxide, and the like, thereby hydrolyzing the 9,11-epoxy linkage, as well as other hydrolyzable substituents present in the molecule. This hydrolysis reaction is conveniently carried out by dissolving the A' -7-acyloxy-9,11-epoxy-cyclopentanopolyhydrophenanthrene compound in an alcoholic solution of the alkali metal hydroxide and heating the resulting solution at the reflux temperature. When a A -7-acyloxy- 9,11 epoxy cyclopentanopolyhydrophenanthrene compound is subjected to these conditions of hydrolysis, there is obtained the corresponding A -7-keto-11 hydroxy-cyclopentanopolyhydrophenanthrene compound such as A J-keto-Il-hydroxy-ergostadiene, A 3 ,1 1-dihydroxy-7-keto-ergostadiene, A -7-keto-11-hydroxy-cholestene, A -3,1 1-dihydroxy-7-keto-cholestene, A -3,11-dihydroxy 7 keto-cholestene, A -3,11-dihydroxy 7 keto-stigmastadiene, A -3,11-dihydroxy-7- keto-cholenic acid, A -3,11-dihydroxy-7-keto-allocholenic acid, A -dihydroxy-7-keto-bisnorcholenic acid, A -3,11-dihydroxy-7-keto-bisnorallocholenic acid, A 3,11-dihydroxy-7-keto-etiocholenic acid, A -3,11-dihydroxy7-keto-etioallocholenic acid, A -3,11-dihydroxy- 7-keto-pregnene, A 3,11-dihydroxy 7 keto-allopregnene, A -7-keto-11-hydroxy-dehydrotigogenin, and the like.

Alternatively, the A' -7-acyloxy-9,1l-epoxy-cyclopentanopolyhydrophenanthrene compound can be reacted with a mild hydrolyzing agent (instead of the alcoholic solution of alkali metal hydroxide) whereupon hydrolysis of the enol acylate and epoxy substituents occur without affecting other hydrolyzable substituents, such as ester linkages, in the molecule. This partial hydrolysis reaction is conveniently conducted by reacting said A' -7-acyloxy 9,11 epoxy cyclopentanopolyhydrophenanthrene compound, at approximately room temperature, with water, or preferably with an aqueous solution of a watermiscible solvent, such as an aqueous solution of acetone, an aqueous solution of a lower aliphatic alcohol such as methanol, ethanol, and the like. This partial hydrolysis reaction is ordinarily utilized for the hydrolysis of A' -7- acyloxy-9,11-epoxy cyclopentanopolyhydrophenanthrene compounds containing at least one additional ester substituent such as A -3,7-diacyloxy-9,1l-epoxy-ergostadiene, A' -3,7-dialkanoxy-9,1l-epoxy-ergostadiene, A 3,7-diacetoxy-9, 1 l-epoxy-ergostadiene, A' -3,7-diacyloxy- 9,11-epoxy-cholestene, A -3,7 dialkanoxy 9,11 epoxycholestene, A -3,7-diacetoxy-9,1l-epoxy-cholestene, A 3,7-diacyloxy 9,11 epoxy-stigmastadiene, A -3,7-dial kanoxy 9,11 epoxy-stigmastadiene, A -3,7-diacetoxy- 9,11-epoxy-stigmastadiene, A' -3,7-diacyloxy-9,1l-epoxycholenic acid, A -3,7-dialkanoxy 9,11 epoxy-cholenic acid, A -3,7-diacetoxy-9,1l-epoxy-cholenic acid, A -3,7- diacyloxy 9,11 4 epoxy-allocholenic acid, A' -3,7-dialka noxy-9,1l-epoxy-allocholenic acid, A' -3,7-diacetoxy-9,11- epoxy-allocholenic acid, A' -3,7-diacy1oxy-9,1l-epoxy-bisnorcholenic acid, A' -3,7-dialkanoxy-9,1l-epoxy-bisnorcholenic acid, A -3,7-diacetoxy-9,1l-epoxy-bisnorcholenic acid, A -3,7-diacyloxy-9,11-epoxy-bisnorallocholenic acid, A' -3,7-dialkanoxy-9,11-epoxybisnorallocholenic acid, N- 3,7-diacetoxy-9,11-epoXy-bisnorallocholenic acid, A -3,7- diacyloxy 9,11 epoxy-etiocholenic acid, A' -3,7-dialkanoxy-9,1l-epoxy-etiocholenic acid, A -3,7-diacetoxy-9,11- epoxy-etiocholenic acid, A -3,7-diacyloxy 9,11 epoxypregnene, A -3,7-dialkanoxy-9,11-epoxy-pregnene, A' -3,7- diacetoxy 9,11 epoxy-pregnene, A -3,7-diacyloxy-9,11- epoxy-allopregnene, A' -3,7-dialkanoxy 9,11 epoxy-allopregnene, A' -3,7-diacetoxy-9,1l-epoxy-allopregnene, A' -7- acyloxy-9,1l-epoxy-dehydrotigogenin acylate, A -alkanoxy-9,1l-epoxy-dehydrotigogenin alkanoate, A7-7-acetoxy-9,1l-epoxy-dehydrotigogenin acetate, and the like. The product obtained by this selective hydrolysis of said A' -7-acyloxy-9,11-epoxy cyclopentanopolyhydrophenanthrene compounds containing at least one additional ester substituent is the corresponding A -7-keto-1lhydroxycyclopentanopolyhydrophenanthrene compound in which the additional ester substituent remains unchanged; thus, the selective hydrolysis of the compounds enumerated hereinabove results, respectively, in the formation of A -3-acyloxy-7-keto-1l-hydroxy-ergostadiene, A -3-alkanoxy-7-keto-1l-hydroxy-ergostadiene, A -3-acetoxy-7-keto-1l-hydroxy-ergostadiene, A 3-acyloxy-7-keto-1l-hydroxy-cholestene, A -3-alkanoxy 7-keto-11-hydroxy-cholestene, A -3-acetoxy-7-keto-11- hydroxy-cholestene, A -3-acyloxy-7-keto-1l-hydroxystigmastadiene, A -3-alkanoxy 7 keto-1 l-hydroxystigmastadiene, 11 -3-acetoXy-7-keto-1l-hydroxy-stigmastadiene, A -3-acyloxy-7-keto-1 l-hydroxy-cholenic acid, A -3-alkanoxy-7-keto-1l-hydroxy-cholenic acid, A -3-acetoxy-7-keto-1l-hydroxy-cholenic acid, A -3 acyloxy-7-keto-1l-hydroxy-allocholenic acid, A -3-alkanoxy-7-keto-1l-hydroxy-allocholenic acid, A -3acet oxy-7-keto-1l-hydroxy-allocholenic acid, A -3-acyloxy- 7-keto-1l-hydroxy-bisnorcholenic acid, A -3-alkanoxy- 7-keto-1l-hydroxy-bisnorcholenic acid, A -3-acetoxy-7- keto-1l-hydroxy-bisnorcholenic acid, A -3-acyloxy-7- keto-11-hydroxy-bisnorallocholenic acid, A -3-alkanoxy-7-keto-11-hydroxy-bisnorallocholenic acid, A -3- acetoxy-7-keto-11-hydroxy-bisnorallocholenic acid, A 3-acyloxy-7-keto-1l-hydroxy-etiocholenic acid, A -3- alkanoxy-7-keto-1l-hydroxy-etiocholenic acid, A -3 acetoxy-7-keto-1l-hydroxy-etiocholenic acid, A -3-acyloxy-7-keto-1l-hydroxy-pregnene, A -3-alkanoxy-7-keto- 11-hydroxy-pregnene, A -3-acetoxy-7-keto-1l-hydroxypregnene, A -3-acyloxy-7-keto 11 hydroxy-allopregnene, A -3-alkanoxy-7-keto 11 hydroxy-allopregnene, A -3-acetoxy-7-keto-1l-hydroxy-allopregnene, A -7- keto-11-hydroxy-dehydrotigogenin acylate, A -7-keto 11-hydroxy-dehydrotigogenin alkanoate, A -7-keto-llhydroxy-dehydrotigogenin acetate.

This A -7-keto-11-hydroxy-cyclopentanopolyhydrophenanthrene compound is then reacted with an acylating agent to produce the corresponding A -7-keto-11-acyloxy cyclopentanopolyhydrophenanthrene compound. The acylation of the A -7-keto-ll-hydroxy-cyclopentanopolyhydrophenanthrene compound is conveniently carried out utilizing a lower aliphatic acid anhydride, such as acetic anhydride, propionic anhydride, and the like, in the presence of a tertiary amine such as pyridine, although other acylating agents can be used if desired. These acylation reactions are preferably calried out at approximately room temperature although higher or lower temperatures can be employed if desired. The A 7 keto 11 acyloxy cyclopentanopolyhydrophenanthrene compounds obtained according to this acylation procedure include the following: A -7-keto-l1-acyloxy ergostadiene, A 3,11 diacyloxy 7 keto ergostadiene, A 3,11 dialkanoxy 7 keto ergostadiene, A809),22 3,11 diacetoxy 7 keto ergostadiene, A 7 keto 11 acyloxycholestene, A 3,11 diacyloxy 7 keto cholestene, 11 3,11 diacetoxy 7 keto cholestene, M69122 3,11 diacyloxy 7 keto stigmastadiene, A 3,11 dialkanoxy 7 keto stigmastadiene, A 3,11 diacetoxy 7 keto stigmastadiene, A 3,11 diacyloxy 7 keto cholenic acid, A -3,11-dialkanoxy-7-keto-cholenic acid, A 3,11 diacetoxy -'7 keto cholenic acid, A 3,11 diacyloxy 7 keto allocholenic acid, A 3,11 dialkanoxy 7 keto allocholenic acid, A86?) 3,11 diacetoxy-7-keto-allocholenic acid, A 3,l1-diacyloxy- 7 keto bisnorcholenic acid, A 3,11 dialkanoxy 7 keto bisnorcholenic acid, A 3,11 diacetoxy 7 keto bisnorcholenic acid, A 3,11 diacyloxy 7 keto bisnorallocholenic acid, A 3,11 dialkanoxy 7 keto bisnorallocholenic acid, A 3,11 diacetoxy 7 keto bisnorallocholenic acid, A 3,11 diacyloxy 7 keto etiooholenic acid, A 3,11 diacyloxy 7.- keto etioallocholem'c acid, A 3,11 diacyloxy 7 keto pregnene, A 3,11- dialkanoxy 7 keto pregnene, A 3,11 diacetoxy 7 keto pregnene, A 3,11 diacyloxy 7 keto allopregnene, A 3,11 dialkanoxy 7 keto allopregnene, A 3,11 diacetoxy 7 keto allopregnene, A 7 keto 11 acyloxy dehydrotigogeninacylate, A 7 keto ll alkanoxy dehydrotigogenin alkanoate, A 7 keto 11 acetoxy-dehydrotigogenin acetate, and the like.

As set forth hereinabove, where it is desired to have an ll-keto substituent in the molecule, the A -7-keto-l1- hydroxy cyclopentanopolyhydrophenanthrene compound is reacted with a strong oxidizing agent, such as chromic acid, thereby forming the corresponding A -7,1l-diketocyclopentanopolyhydrophenanthrene compound. This oxidation reaction, where chromic acid is used as the oxidizing agent, is conveniently carried out by dissolving the 7 keto 9,11 epoxy cyclopentanopolyhydrophenanthrene compound in acetone, adding to the resulting solution a solution containing chromic acid dissolved in aqueous sulfuric acid, and allowing the mixture to react at substantially room temperature for a period of approximately one hour. In accordance with this procedure, there is obtained the desired A -7,11-diketo-cyclopentanopolyhydrophenanthrene compound such as 13 7,11 diketo ergostadiene, A 3 acyloxy 7,11 diketo ergostadiene, A 3 alkanoxy 7,11 diketo ergostadiene, A 3 acetoxy 7,11 diketoergostadiene, A 7,11 diketo cholestene, 11 3 acyloxy 7,11 diketo cholestene, A 3 alkanoxy 7,11 diketo cholestene, A 3 acetoxy 7,11 diketo cholestene, AS69122 3 acyloxy 7,11 diketo stigmastadiene, A 3 alkanoxy 7,11 diketo stigmastadiene, AW),22 3 acetoxy 7,11 diketo stigmastadiene, 11 3 acyloxy 7,11 diketo cholenic acid, A803) 3 alkanoxy 7,11 diketo cholenic acid, A 3 acetoxy 7,11 diketo cholenic acid, 43 3 acyloxy 7,11 diketo allocholenic acid, A 3 alkanoxy 7,11 diketo allocholenic acid, A 3 acetoxy 7,11 diketo allocholenic acid, [3 3 acyloxy 7,11 diketo bisnorcholenic acid, A 3 alkanoxy 7,11 diketo bisnorcholenic acid, A 3 acetoxy 7,11 diketo bisnorcholenic acid, A 3 acyloxy 7,11 diketo bisnorallocholenic acid, A 3 alkanoxy 7,11 diketo bisnorallocholenic acid, A 3 acetoxy 7,11 diketo bisnorallocholenic acid, A 3 acyloxy 7,11 diketo etiocholenic acid, A 3 acyloxy 7,11 diketo etiocholenic acid, A 3 acyloxy 7,11 diketo pregnene, A 3 alkanoxy 7,11 diketo pregnene, A 3 acetoxy 7,11 diketo pregnene, 13 3 acyloxy 7,11 diketoallopregnene, A 3 alkanoxy 7,11 diketo allopregnene, A 3 acetoxy 7,11 diketo allopregnene, A 7,11 diketo dehydrotigogenin acylate, A 7,11 diketo dehydrotigogenin alkanoate, A 7,11 diketo-dehydrotigogenin acetate, and the like.

The A -3,11-dihydroxy-7-keto-cyclopentanopolyhydrophenanthrene compounds (Compound 6 hereinabove) are readily converted to steroid hormones having an oxygen atom attached to the ll-carbon atom as follows: the A -3,11-dihydroxy-7-keto cyclopentanopolyhydrophenanthrene compound is reacted with zinc and acetic acid thereby forming the corresponding 3,11-dihydroxy- 7 keto cyclopentanopolyhydrophenanthrene compound, which is heated with a diethylene glycol solution of hydrazine and potassium hydroxide to produce the corresponding 3,11 dihydroxy cyclopentanoperhydrophenanthrene compound; this 3,11-dihydroxy-cyclopentanoperhydrophenanthrene compound is then treated according to known methods (the exact method of treatment depending upon the side chain attached to the l7-carbon atom) to convert the organic substituent attached to the 20- carbon atom to a keto radical thus forming the corresponding 3,11-dihydroxy-20-keto-pregnane. (For example, where the side chain attached to the 17-carbon atom is that present in the bile acid,,bisnorallocholanic acid, the 3,11-dihydroxybisnorallocholanic acid is esterified, the methyl 3,11-dihydroxy-bisnorallocholanate is reacted with phenyl magnesium iodide to form 3,11-dihydroxy-20 allopreganyl diphenyl carbinol; the latter compound is reacted with acetic anhydride to produce 3,1 l-diacetoxy-allo etiocholanyl-methyl-diphenylethylene, and this compound is treated with ozone to form 3,11- diacetoxy-ZO-keto-allopregnane.) This 3,11- diacetoxy- 20-keto-allopregnane (obtained as described above starting with 3,11-dihydroxy bisnorallocholanic acid, or if preferred, by degrading the side chain of some other 3,11- dihydroxycyclopentanoperhydrophenanthrene compound) is then reacted with acetic anhydride in the presence of p-toluene sulfonic acid catalyst thereby forming the corresponding A -3,11,20-triacetoxy-pregnene; this com pound is reacted with perbenzoic acid to form 3,11-diacyloxy-17-hydroxy-20-keto-allopregnane; the latter compound is then reacted with bromine followed by sodium acetate thereby forming the corresponding 3,11,20-triacetoxy-17-hydroxy-20-keto-allopregnane which, upon reaction with a hydrolyzing agent followed by a partial esterification, yields the corresponding 3,11,17-trihydroxy- 20-keto-21-acetoxyallopregnane; the 3,11,17-trihydroxy- ZO-keto-Zl-acetoxy-allopregnane is then reacted with chromic acid thereby forming 3,11,20-triketo-l7-hydroxy- 2l-acetoxy-allopregnane which is reacted with two molecular equivalents of bromine followed by rearrauge ment to produce the corresponding 2,4-dibromo-3,11,20 triketo-17-hydroxy-2l-acetoxy-allopi'egnane; this compound is reacted with a dehydrohalogenating agent and a reducing agent to form cortisone acetate, i.e. A -3,11,20- triketo-17-hydroxy-2l-acetoxy-pregnene.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 Four hundred milligrams of A -3-hydroxy-7-ketoergostadiene (which can be prepared, starting with ergosterol D acetate, in accordance with the procedure set forth in column 3, line 62 to column 4, line 5 9 hereinabove and described more particularly in a copending application of the present applicant, Serial No. 240,051, filed August 2, 1951, now abandoned) were mixed with 1 cc. of acetic anhydride and 1 cc. of acetyl chloride, and the mixture was heated under reflux for a period of about one hour. The solvents were evaporated from the reaction mixture to give crude A -3,7-diacetoxy-ergostatriene which was obtained as a yellow gum;

A max. 237 mu, E1 247, A max. 241 mu. Eff? 252 Example 2 A mixture containing 1 gram of A -3-hydr0xy-7-ketoergostadiene, 20 cc. of acetic anhydride and 20 cc. of acetyl chloride was heated under reflux for a period of about one hour. The solvents were evaporated from the reaction mixture in vacuo to give crude A -3,7-diacetoxyergostatriene. This material 'was dissolved in 25 cc. of benzene, and to this solution was added 15.5 cc. of a solution of perbenzoic acid in benzene having a normality of 0.375. The resulting solution was allowed to stand at room temperature for a period of about twelve hours, the reaction solution was extracted with an aqueous solution of sodium hydroxide, then with water, and dried. The dry benzene solution was evaporated in vacuo to give crude A -3,7-diacetoxy-9,ll-epoxy-ergostadiene as a residual gum.

This material was subjected to chromatographic purification utilizing ether-petroleum-ether as the eluting sol- 11 vent to give substantially pure A' -3,7-diacetoxy-9,11- epoxy-ergostadiene.

AnaZysis.-Calcd for C H O C, 74.96; H, 9.43. Found: C, 74.43; H, 9.17.

Example 3 Example 4 One hundred milligrams of A -3,7-diacetoxy-9,1lepoxy-ergostadiene was dissolved in a 1 N solution of sodium hydroxide in methanol, and the resulting solution was heated under reflux for a period of one hour. The resulting solution was diluted with water, and the crystalline material which separated was recovered by filtration to give crude A -3,11-dihydroxy-7-keto-ergostadiene. This material was purified by recrystallization from acetone to give 90 mg. of substantially pure M -3,11-dihydroxy-7-keto-ergostadiene which was ob- 12 Anizlysia-Calcd for C H O C, 78.46; H, 10.34. Found: C, 78.20; 10.24.

Example 5 One hundred milligrams of A -3,1 1-dihydroxy-7-ketoergostadiene, prepared substantially as described in Example 4, hereinabove, were dissolved in 2 cc. of pyridine containing one cc. of acetic anhydride and the resulting solution was allowed to stand at room temperature for approximately six hours. The acetylation mixture was evaporated in vacuo and the residual material was recrystallized from methanol to give needles of A 3,11 diacetoxy 7 keto ergostadiene; M.P. 176 177 C.

Analysis.Calcd for C H O C, 74.96; H, 9.43. Found: C, 74.94; H, 9.50.

Example 6 One hundred and sixty milligrams of A -3-acetoxy- 7-keto-1l-hydroxy-ergostadiene, prepared substantially as described in Example 3 hereinabove, were dissolved in 10 cc. of acetone and to this solution was added a solution containing 23 mg. of chromic acid in 1 cc. of 2 N sulfuric acid. The resulting mixture was allowed to react at room temperature for a period of approximately one hour, and the acetone was evaporated from the reaction mixture in vacuo. The residual material was diluted with water, and the crystalline material which separated was recovered by filtration and dried to give crude A -3-acetoxy-7,1l-diketo-ergostadiene; M.P. 126 C. This material was recrystallized from ethanol to give 90 mg. of substantially pure A -3-acetoxy-7Jl-diketotained in the form of silky needles; M.P. 213-215" C.; 35 ergostadiene; M.P. -136 C.; x max. 265 m E% 193 A max. 255 mu; E% 197 (alcohol). (iso-octane).

Example 7 HaC CH3 0 0 0. I I O CHsCOO CHaCOO H H Compound 18 Compound 19 l Aqueous H2504 H3?3 CH8 HBFKD-CH: O O i O 0 HO 0 HO =0 Compound 20 Compound 21 CH: HaC CHa O O I l Perbenzoic O CH C O O O C O CH CHaC 0 V OCOCH; 3 a H H Compound 23 Compound 22 lags Aqueous Methanol HaC -CHa H O CH Chromie acid OH3COO I =0 CHBCOO =0 a. I I E Compound 24 Compound 25 The A -bisdehydrotigogenin acetate epoxide utilized as the starting material in the following example can be prepared according to the procedure set forth in detail in co-pending applications, Serial No. 213,807, filed March 3, 1951, now US. Patent No. 2,840,574, and Serial No. 215,026, filed March 10, 1951, now abandoned. In that procedure, diosgenin-3 acetate is reacted with N- bromosuccinimide and the resulting 7-bromodiosgenin-3 acetate is heated with collidine thereby forming A dehydrodiosgenin-3 acetate, the A -dehydrodiosgenin-3 acetate is reacted with hydrogen in the presence of Raney nickel catalyst thereby forming M-dehydrotigogenin acetate, the latter compound is treated with mercuric acetate in glacial acetic acid to produce the A'wun-bisdehydrotigogenin acetate, and said A bisdehydrotigogenin acetate is reacted with perbenzoic acid in benzene solu tion thereby forming the desired A' -bisdehydrotigogenin acetate epoxide.

A hot solution of 1.0 g. of the A' -bisdehydrotigogenin acetate epoxide (compounds 18 and 19) in 60 cc. of dioxane was diluted with cc. of water. Two cubic centimeters of a 2 N aqueous solution of sulfuric acid was added to the aqueous .dioxane solution, and the resulting mixture was heated to a temperature of about 90-100 C. for a period of approximately twelve hours. At the end of this heating period, the reaction mixture was evaporated substantially to dryness to give a mixture of A and -7-keto-dehydrotigogenin (compounds 20 and 21). This mixture was dissolved in a mixture of 20 cc. of acetic anhydride and 20 cc. of acetyl chloride, and the resulting solution was heated under reflux for a period of about four hours. The solvents were removed from the reaction mixture by evaporation in vacuo to give the crude enol acetate, A' -7-acetoxydisdehydrotigogenin acetate (Compound 22).

This crude enol acetate was dissolved in 25 cc. of benzene, and to this solution was added 10 cc. of an 0.5 N solution of perbenzoic acid in benzene. The resulting mixture was allowed to stand at room temperature for approximately six hours, and the benzene reaction solution was extracted with a sufiicient quantity of a 2 N aqueous solution of sodium hydroxide to remove acidic products. The benzene solution was then dried and the solvents evaporated therefrom in vacuo to give A -7- acetoxy-9,1l-epoxy-dehydrotigogenin acetate Compound 23).

The latter product was .dissolved in 50 cc. of methanol containing 2 cc. of water, and the solution was allowed to stand at room temperature for a period of approximately twelve hours. The solvents were then evaporated from this solution in vacuo to give A -7-keto-11-hydroxy-dehydrotigogenin acetate (Compound 24).

The latter product was dissolved in 50 cc. of acetone and to the solution was added a solution containing 230 mg. of chromium trioxide dissolved in 10 cc. of 0.72 N aqueous sulfuric acid. The resulting mixture was allowed to stand at room temperature for a period of about one hour. The reaction mixture was then diluted with water, and the crystalline material which separated was recovered by filtration, dried and purified by recrystallization from methanol to give substantially pure A -7,11-diketo-dehydrotigogenin acetate (Compound 25); MP. 226-227 C.; a =l4 (chloroform).

Example 8 Two grams of methyl A' -3-acetoxy-choladienate epoxide (which can be prepared as described in co-pending application Serial No. 215,026, filed March 10, 1951) were suspended in 20 cc. of acetic anhydride, and the suspension was heated in a sealed tube at a temperature of C. for a period of about four hours. The reaction solution was cooled to room temperature whereupon large rectangular crystalline plates separated from the solution. This crystalline material was recovered by filtration, washed with acetic anhydride and dried to give about 1.1 g. of crude methyl A -3-acetoxy-7-ketocholenate; M.P. 168170 C. This material was purified by chromatography followed by recrystallization from acetic anhydride to give substantially pure methyl A 3-acetoxy-7-keto-cholenate; Ml. C.

One gram of crude methyl A -3-acetoxy-7-ketocholenate, prepared as described above, was dissolved with heating in 20 cc. of acetic anhydride and 20 cc. of acetyl chloride, and the solution was heated under reflux for about one hour. The reaction solution was evaporated under reduced pressure to give methyl A -3,7-diacetoxy-choladienate which was obtained in the form of a syrup which absorbs in the ultra-violet at 2430 A.;

Efg ,=252 Example 9 A suspension of 1.34 g. (0.003 moles) of methyl M -3-acetoxy-choladienate epoxide in 20 cc. of acetic anhydride was heated in a sealed tube at 150 C. for

Example One and forty-six one-hundredths grams (0.003 mole) of methyl A -3,7-diacetoxy-choladienate, prepared as described in Example 9 hereinabove, was dissolved in 25 cc. of benzene and the solution was cooled to C. A benzene solution (10.3 cc.) containing 0.003 mole of perbenzoic acid was added over a period of fifteen minutes to the solution containing the methyl A' -3,7-diacetoxy-choladienate, and the resulting solution was maintained at room temperature for a period of about fifteen hours. The benzene reaction solution was extracted with a 5% aqueous solution of potassium hydroxide thereby removing acidic material, and the benzene layer was then extracted with water until neutral. The benzene solution was dried over anhydrous sodium sulfate and evaporated in vacuo to give methyl A -3,7dlElC6t0XY-9,11- epoxy-cholenate.

The methyl A 3,7 diacetoxy-9,1l-epoxy-cholenate, prepared as described above, was dissolved in 7 cc. of 85% aqueous methanol and the solution was allowed to stand at room temperature for approximately twentyfour hours. The solvent was then evaporated in vacuo and the residual material was triturated with ether. The crystalline product was recovered by filtration and dried to give 0.14 g. of methyl A -3-acetoxy-7-keto-1l-hydroxy-cholenate. This material was purified by recrystallization from ethyl acetate to give substantially pure methyl A 3 acetoxy 7 keto-l l-hydroxy-cholenate; M.P. 171173 C. Analysis.-Calcd for C27H400 i C, 70.40; H, 8.75. Found: C, 70.37; H, 8.98. x max. 2540 A.,

i tm. n -=+8 (chloroform) Example 1] Thirty milligrams of chromium trioxide were dissolved in 0.3 cc. of 10% aqueous sulfuric acid, and the solution was added, with stirring at a temperature of about C., to a solution containing 100 mg. of methyl A 3-acetoxy-7-keto-1l-hydroxy-cholenate dissolved in 10 cc. of acetone. The resulting mixture was stirred at a temperature of 20 C. for a period of one hour, and the insoluble chromium residue was removed by filtration and washed with a small volume of acetone. This filtered acetone solution and washings were added to 100 cc. 0 ice water, and the crystalline material which precipitated was recovered by filtration, washed free of acid with water and dried to give 80 mg. of methyl A -3-acetoxy- 7,11-diketo-cholenate. This material was recrystallized from ethanol to give substantially pure methyl A -3- acetoxy-7,1l-diketo-cholenate; M.P. 114115 C. Analysis.Calcd for C H O C, 70.70; H, 8.35. Found: C, 70.93; H, 8.30. [a] =+42 (chloroform); A max. 2710 A.,

i tm. 183

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of my inventron.

I claim:

1. A -7-keto-11-oxygenated-cyclopentanopoly-hydrophenanthrene compounds selected from the group which consists of A -3,l1-dihydroxy-7-keto-ergostadiene, A -3,1l-bis (lower alkanoyloxy)-7-keto-ergostadiene, 13 -3-( lower alkanoyloxy) -7-keto-1 l-hydroxy-ergostadiene, lower alkyl A -3,11-dihydroxy-7-keto-cholenate, and lower alkyl A -3-(lower alkanoyloxy) -7-keto-l1- hydroxycholenate.

2. M 3,11 dihydroxy-7-keto ergostadiene having the formula:

3. A -3,11 diacetoxy-7-keto ergostadiene having the formula:

4. Methyl A -3-acetoxy-7-keto-11 hydroxycholenate having the formula:

CHJCOO O 5. A? -3-acetoxy-7-ketoll-hydroxy ergostadiene having the formula:

t CH-CHzCHzC O O CH 6. The process which comprises reacting a A' -7- acyloxy-9,11-epoxy cyclopentanopolyhydrophenanthrene compound with a hydrolyzing agent comprising an alcoholic solution of an alkali metal hydroxide to form the corresponding A -7-keto-1l-hydroxy-cyclopentanopolyhydrophenanthrene compound, and reacting the latter compound with an acylating agent comprising a lower aliphatic acid anhydride to form the corresponding A 7-keto-l1 acyloxy cyclopentanopolyhydrophenanthrene compound.

7. The process which comprises reacting a A -7- acyloxy-9,11-epoxy cyclopentanopolyhydrophenanthrene compound with a hydrolyzing agent comprising an alcoholic solution of an alkali metal hydroxide to form the corresponding A -7-keto-1l-hydroxy-cyclopentanopolyhydrophenanthrene compound, and reacting the latter compound with an oxidizing agent comprising chromic acid to form the corresponding A -7,11-diketo-cyclopentanopolyhydrophenanthrene compound.

8. The process which comprises reacting A -3,7-di acetoXy-9,1l-epoxy-ergostadiene with a hydrolyzing agent comprising an alcoholic solution of an alkali metal hydroxide followed by an acetylating agent to produce 11 -3 ,11-diacetoXy-7-keto-ergostadiene.

9. The process which comprises reacting A' -7-acetoxy- 9,1l-epoxy-dehydrotigogenin acetate with a mild hydrolyzing agent comprising an aqueous solution of a lower alkanol followed by chromic acid to form A 7,1l-diketo-dehydrotigogenin acetate.

10. The process which comprises reacting methyl A 3,7-diacetoxy-9,1l-epoxy-cholenate with a mild hydrolyzing agent comprising an aqueous solution of a lower alkanol to produce methyl A -3-acetoXy-7-keto-1lhydroxy-cholenate, and reacting the latter compound with chromic acid to form methyl A -3-acetoxy-7,1l-diketocholenate.

11. The process which comprises reacting a A' -7- acetoxy-9,11-epoxy cyclopentanopolyhydrophenanthrene compound with a hydrolyzing agent comprising an alcoholic solution of an alkali metal hydroxide to produce the corresponding A -7-keto-1l-hydroxy-cyclopentanopolyhydrophenanthrene compound.

12. The process which comprises reacting at A 7- acyloxy-9,11-epoxy cyclopentanopolyhydrophenanthrene compound with an alcoholic solution of an alkali metal hydroxide to produce the corresponding A -7-keto-11- hydroxy-cyclopentanopolyhydrophenanthrene compound.

13. The process which comprises reacting a A"-3,7-diacyloxy 9,11 epoxy cyclopentanopolyhydrophenanthrene compound with an aqueous solution of a lower alkanol thereby producing the corresponding M -3- acyloxy 7 keto 11 hydroxy cyclopentanopolyhydrophenanthrene compound.

14. The process which comprises reacting A' -Ia'J-diacetoxy-9,1l-epoxy-ergostadiene with a mild hydrolyzing agent comprising an aqueous solution of a lower alkanol to produce A --3-acetoxy-7-keto-1l-hydroxy-ergostadi- GM.

15. The process which comprises reacting M -3- 18 acetoxy-7-keto-1l-hydroxy-ergostadiene with a methanolic solution of sodium hydroxide to produce A -3,11-dihydroxy-7-keto-ergostadiene.

16. The process which comprises reacting A -3,7- diacetoxy-9,1l-epoxy-ergostadiene with a methanolic solution of sodium hydroxide thereby forming M -3,11- dihydroxy-7-ketorergostadiene.

17. The process which comprises reacting A"-7-acetoxy- 9,1l-epoxy-dehydrotigogenin acetate with a mild hydrolyzing agent comprising an aqueous lower alkanol to produce A -7-keto-1 1-hydroxy-dehydrotigogenin acetate.

18. The process which comprises reacting A -7-keto- 11-hydroxy-dehydrotigogenin acetate with an alcoholic solution of an alkali metal hydroxide to produce A -7- keto- 1 l-hydroxy-dehydrotigogenin.

19. The process which comprises reacting methyl A"- 3,7-diacetoxy-9,1l-epoxy-cholenate with aqueous methanol thereby forming methyl A -3-acetoxy-7-keto-11-hy droxycholenate.

20. The process which comprises reacting a A -7- keto 11 hydroxy cyclopentanopolyhydrophenanthrene compound with an acylating agent comprising a lower aliphatic acid anhydride to form the corresponding A 7 keto 11 acyloxy cyclopentanopolyhydrophenanthrene compound.

21. The process which comprises reacting [d -3,11- dihydroxy-7-keto-ergostadiene with an acetylating agent to form A ll1-diacetoxy-7-keto-ergostadiene.

22. The process which comprises reacting cl 3- acetoxy-7-keto-1l-hydroxy-ergostadiene with chromic acid thereby forming A -3-acetoxy-7,1l-diketo-ergostadiene.

23. The process which comprises reacting A -7-keto- 1l-hydroxy-dehydrotigogenin acetate with chromic acid thereby forming A -7,1l-diketo-dehydrotigogenin acetate.

24. The process which comprises reacting methyl A 3-acetoxy-7-keto-ll-hydroxy-cholenate with chromic acid to produce A -3-acetoxy-7,1l-diketo-cholenate.

No references cited. 

1. $8(9)-7-KETO-11-OXYGENERATED-CYCLOPENTANOPOLY-HYDROPHENANTHRENE COMPOUNDS SELECTEDF FROMT EH GROUP WHICH CONSISTS OF $8(9),22-3,11-DIHYDROXY-7-KETO-ERGOSTADIENE, $8(9),22-3-(LOWER ALKANOYLOXY) -7KETO-11HYDROXY-ERGOSTA $8(9),22-3-(LOWER ALKANOYLOXY)-7-KETO-11-HYDROXY-ERGOSTADIENE, LOWER ALKYL $8(9)-3-(LOWER ALKANOYLOXY)-7-KETO-11AND LOWER ALKYL $8(9)-3-(LOWER ALKANOYLOXY)-7-KETO-11HYDROXYCHOLENATE.
 17. THE POROUS WHICH COMPRISES REACTING $7-7-ACETOXY9,11-EPOXY-DEHYDROTIGOGENIN ACETATE WITH A MILD HYDROLYZING AGENT COMPRISING AN AQUEOUS LOWER ALKANOL TO PRODUCE $8(9)-7-KETO-11-HYDROXY-DEHYDROTIGOENIN ACETATE. 